706_S2006_PS8key - 7.06 Problem Set #8, 2006 - KEY 1. You...

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1 7.06 Problem Set #8, 2006 -- KEY 1. You are working in a cancer research lab studying tumorigenesis in mice. a) There are lots of genes that your lab might study! List all of the genes in the following pathways that we have learned about throughout the semester that are oncogenes, and all of the genes that are tumor suppressor genes. i) The Wingless pathway ii) The RTK/Ras pathway The Wingless pathway is: Wnt/Wg Frizzled Dishevelled --] GSK3/APC/Axin --] beta-catenin target genes Activation of this pathway by Wnt stimulates the transcription of genes that drive the cell cycle. Thus constitutive signaling through this pathway would lead to over-proliferation. Wnt, Frizzled, Dishevelled, and beta-catenin promote growth by acting positively in the pathway, so all of these genes could be oncogenes. The GSK-3/APC/Axin proteins act to inhibit beta-catenin when the pathway is not being stimulated. Thus, for instance, the APC gene is a tumor suppressor gene, because if you lose function in APC, beta-catenin will always be active and the growth-promoting target genes will always be transcribed. The RTK/Ras pathway is: Growth factor ligand RTK GRB2 Sos Ras Raf MAPKK/MEK MAPK target genes Activation of this pathway by growth factors stimulates the transcription of genes that drive the cell cycle. Thus constitutive signaling through this pathway would lead to over- proliferation. All of the genes listed above promote growth by acting positively in the pathway, so all of these genes could be oncogenes. The 14-3-3 proteins sequester Raf in the cytosol when the pathway is not being stimulated. The 14-3-3 gene is a tumor suppressor gene, because if you lose function in 14-3-3, Raf will always be free to phosphorylate MAPKK/MEK, and thus the growth-promoting target genes will always be transcribed. b) One of the assays your lab uses is the soft agar colony forming assay. What is the principle behind this assay? Wild-type fibroblasts require adhesion for their growth and proliferation. Cancer cells, on the other hand, display adhesion-independence. In soft agar, there is no adhesion between cells and the substratum, and hence only cancer cells will grow and divide enough to form colonies. c) One of the genes studied in your lab is E2F, which is a transcripton factor that controls the G1 to S transition in mammals. i) How is E2F normally regulated in the cell?
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2 E2F is normally held inactive by the Rb proteins so that E2F cannot activate transcription of genes that promote the passage into S phase. ii) How can E2F be inappropriately activated to lead to cancer? E2F can acquire a mutation such that it no longer interacts with Rb. In the absence of Rb binding, E2F acts a transcription factor for genes required for G1-S transition even when the cell cycle is not supposed to occur. iii)
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706_S2006_PS8key - 7.06 Problem Set #8, 2006 - KEY 1. You...

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